PONE-D-24-10048Association Between Hypertriglyceridemia and Depression : A Systematic Review and Meta-AnalysisPLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: No

Reviewer #2: No

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript by Di-Ru Xu and colleagues aims to synthesise current evidence on the differences in triglyceride (TG) concentrations between patients with major depressive disorder (MDD) and healthy controls (HCs), by conducting a systematic review and meta-analysis (MA).

This is a very relevant topic for clinical psychiatry given the close relationship between mental disorders, metabolic alterations, cardiovascular risk, and mortality.

Nevertheless, the MA presents some methodological issues that need to be taken into consideration before publication.

MAYOR COMMENT:

The inclusion criteria are not clear: On page 4, Section 2.2 Study selection, you define "3) inclusion of a depressed group diagnosed by DSM (III/IV/V), CCMD, or ICD-10," however, it is not clear whether only patients with MDD are included or also other diagnoses. In Section 2.1 Search strategy, you include terms such as "depressive symptom" and "dysthymia" in your search string. Please clarify this point. If diagnoses other than MDD are included, it is necessary to modify the entire manuscript to refer to "depressive disorders" rather than MDD. Additionally, in Table 1, the diagnoses made in each study should be reported (this is probably another source of heterogeneity?).

The comparator is not clear either. On page 4, Section 2.2 Study selection, you define "3) inclusion of a psychiatrically healthy group." Apart from the fact that this should be criterion number 4, there are some issues with this definition: 1) "Psychiatrically" implies that patients may have medical disorders? This could be another source of heterogeneity. Please clarify this point, and if patients have medical disorders, report them in Table 1. In any case, avoid using the term "psychiatrically." How were healthy controls defined (DSM/ICD?, none?)?

It's not clear how heterogeneity exploration was handled.

The authors report having conducted both meta-regression and subgroup analysis for age, gender, and BMI. While it may make sense to perform both subgroup analysis and meta-regression for the same variables in a meta-analysis, it's important to consider a few issues:

1) Analysis objective: Subgroup analysis and meta-regression serve different purposes. Particularly for the age variable, I don't understand the rationale behind conducting subgroup analysis by dividing into age < or > 45 years. Are there any specific evidences suggesting triglyceride levels change specifically above 45 years? Also, how were these 45 years considered? Based on the mean age of the studies or inclusion criteria of the primary studies? The analysis should be conducted based on the latter. Please reconsider conducting subgroup analysis, favoring meta-regression. For BMI, I think it may make sense to conduct both meta-regression and subgroup analysis because studying the difference between normal-weight and overweight patients makes sense (unlike age 45), but the same considerations regarding mean of the studies or inclusion criteria apply. Specify it.

2) Data availability regarding sex: If you have access to the number of males and females, and thus the percentage of males and females, it makes much more sense to conduct only a meta-regression that includes many studies, rather than a subgroup with few studies and therefore less reliable results. Please consider conducting only meta-regression and not subgroup analysis (only 7 studies out of 46). In general, it is always better to conduct further analyses when you have at least 10 studies.

Furthermore, the purpose of a subgroup analysis is also to test the difference between the identified groups (Test for subgroup differences). The authors only report the effect sizes for the two subgroups without stating whether these differences are significant based on the test. Therefore, it cannot be concluded that the variable (age, BMI, medication use, sex) significantly moderates the effect. Please report the Test for subgroup differences. Indeed, the directions of the effect do not seem to be very different, and there may be no differences between the groups studied. This would be compatible and consistent with the results of the meta-regressions.

3) In addition to these analyses, other variables should be taken into consideration. The effect of medication use has only been considered based on whether patients are taking medication or not. Another important factor is which medications they are taking. It's not uncommon for major depressive disorder patients to be prescribed medications such as second-generation antipsychotics (olanzapine, quetiapine) that are associated with metabolic alterations. Was it possible to consider this variable? Other important variables would include the study date and the country of the study. There could be year and regional differences to take into account.

Plase, conduct these analyses.

Study degign: Why did you include only observational studies and not RCTs?

Please provide the protocol registration number.

MINOR MINOR COMMENTS:

The word 'hypertriglyceridemia' appears in the title. I don't think it's correct. The meta-analysis compares triglyceride levels between MDD and HCs. As the authors themselves emphasize in the discussion, the values often fall within normal ranges in both groups.

In the abstract, it is redundantly repeated that meta-regressions and subgroup analyses were conducted to investigate heterogeneity.The use of the word "covariate" in reference to meta-regressions is not correct.

In both the abstract and results sections, why use the word "approximately"? It's not approximate; it's your result. Just report the effect size and the 95% CI.

Throughout the manuscript, please use the word "sex" (biologically determined) instead of "gender" (socially and culturally determined).

Among the inclusion criteria, you only mention ICD-10 for diagnosis and not other versions. Why? Did you find only this, or was a diagnosis with ICD-9 not considered? I believe it's the former, but the criteria should be a priori.

You mentioned that data were not available for 33 studies. In these cases, did you reach out to the authors?

Reviewer #2: Dear all,

Thank you for sending the paper titled "Association Between Hypertriglyceridemia and Depression: A Systematic Review and Meta-Analysis" and for allowing me to review it. The authors conducted a meta-analysis to evaluate the disparity in blood triglyceride concentrations between individuals with depression and healthy controls. They concluded that triglyceride levels were elevated in those with depression compared to the control group.

Below I will detail my concerns and/or suggestions to improve this paper:

1. Could you please provide a clearer definition of your study population (cases)? It appears that you are interested in examining individuals with major depressive disorder (as defined by DSM, ICD, or CCD criteria). However, it's not explicitly stated whether your inclusion criteria encompassed only those with a confirmed diagnosis of major depressive disorder, or if you also intended to include individuals with depressive symptoms or dysthymia (as indicated in the search string).

2. I don’t understand your exclusion criteria depressive symptoms in the context of medical illnesses (e.g., hyperlipemia, dyslipidemia). Are you interested in observing the differences in tryglicerides between people without a diagnosis of hypertriglyceridemia? Please, specify.

3. The authors used the mean difference as the effect size, which offers clinical insight into the disparity in triglyceride levels between the two populations. However, I believe it would be useful to also include a standardized mean difference, which could facilitate comparison of your findings with those of other studies.

4. Please, provide in the supplemental material a list of the studies that were excluded at the full-text assessment, with reasons, as required by PRISMA guidelines.

5. Did you have a prepublished protocol? If not, this should be considered as an important limitation.

6. The cut-offs chosen for subgroup analyses seem to be quite arbitrary (especially without a protocol). Please, provide the reasons behind choosing these specific cut-offs.

7. The authors present both subgroup analyses and meta-regressions. However, both subgroup analyses and meta-regressions follow the same underlying logic. Furthermore, in their reporting of the subgroup analysis regarding age (comparing individuals aged more and less than 45 years), they omit the comparison statistic between the two subgroups, which, according to the meta-regression, should not be significant. I suggest to revise this aspect and consistently include a statistic comparing the two subgroups, or alternatively, solely report the meta-regressions.

I hope that these suggestions may help improving the manuscript.

Best wishes,

Reviewer

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Reviewer #1: No

Reviewer #2: No

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Association Between Triglyceride and Depression: A systematic Review and Meta-analysis

PONE-D-24-10048R1

Dear Dr. yu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Md. Rabiul Islam, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I've reviewed your revised manuscript and the comments from the reviewers, and I think all of the concerns raised have been satisfactorily addressed.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I thank the authors for adequately responding to my review, I have no more comments and I reccomend the manoscript for publication

Reviewer #3: The author answered all the reviewer comments carefully. They corrected their manuscript accordingly. I think we can accept this paper for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

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